Cyanoethyl ergolene and ergoline
derivatives



United States Patent Ofiice 3,232,943 Patented Feb. 1, 1966 3,232,943 CYANOETHYL ERGOLENE AND ERGOLINE DERIVATIVES Albert Hofman and Franz Troxler, both of Bottmingen, Basel-Land, Switzerland, assignors to Sandoz Ltd. (also known as Sandoz A.G.), Basel, Switzerland N Drawing. Original application Nov. 5, 1962, S'er. No. 235,559. Divided and this application Nov. 19, 1964, Ser. No. 412,314

5 Claims. (Cl. 260-2855) The present invention relates to new ergolene and ergoline derivatives, their acid addition salts, and pharmaceutical compositions containing as an essential active ingredient a said new ergolene or ergoline derivative or a non-toxic pharmaceutically acceptable acid addition salt in an inert carrier or vehicle prepared in unit dosage form. This application is a division of copending application Serial No. 235,559 filed November 5, 1962.

The present invention provides compounds of the formula:

C Ha

in which R is an alkoxycarbonyl, dialkylcarbamoyl, hydroxyalkylcarbamoyl, dialkylureido or alkoxycarbonylamino radical, whereof the alkyl portion in each radical contains from one to four carbon atoms inclusive, a hydroxymethyl radical or a carbonyl radical substituted with the tripeptide radical of a natural ergot alkaloid of the peptide type, and

their acid addition salts, and pharmaceutical compositions containing, in addition to an inert carrier or vehicle, a Compound I and/ or an acid addition salt thereof.

The Compounds I and their acid addition salts are produced by reacting a compound of the formula:

have the above significance, with acrylonitrile in the presence of a proton acceptor and, when an acid addition salt is required, salt formation is efiected with an organic or inorganic acid in a manner per se known.

Suitable acids for salt formation are, for example, hydrochloric, hydrobromic, hydriodic, sulfuric, citric, tartaric, succinic, maleic, malic, acetic, oxalic, benzoic, fumaric, gallic, hexahydrobenzoic, methauesulfonic and phosphoric acids.

The possibilities of obtaining variations of the lysergic acid molecule and its derivatives, the most important of which are the natural ergot alkaloids and their 9,10- dihydro compounds, by chemical substitution, are very limited. Chemical conversions are difficult because of the tendency of the lysergic acid molecule to decompose due to its susceptibility towards acids, bases and oxidation agents and even to the oxygen of the air and, light and because of the ease with which isomers are formed. It was thus surprising to find that a cyanoethyl radical could readily be introduced into the 1-position of the lysergic acid molecule.

The production of Compounds I may, for example, be elfected by dissolving a Compound II in a suitable solvent such as dioxane and reacting it with acrylonitrile in the presence of a proton acceptor, e.g., sodium methylate, sodium ethylate or benzyl trimethylammonium hydroxide, at room temperature or higher. Alcohols have been found to be unsuitable as solvents as they themselves react with acrylonitrile to some extent. Acrylonitrile itself may also be used as the solvent and while the starting materials sometimes do not initially readily dissolve therein they generally go into solution satisfactorily during the course of the reaction.

For the purpose of isolation, the reaction mixture is preferably taken up and shaken in a binary solvent mixture, e.g., ether/ aqueous tartaric acid. The desired Compound I is obtained from the acidic aqueous layer, isolation and purification being effected in accordance with known methods, e.g., by chromatography on aluminum oxide and/ or recrystallization.

When acrylonitrile is used as the solvent and a solid alkali metal alcoholate as the proton acceptor, the latter may simply be filtered otf, the acrylonitrile evaporated and its polymerization products separated by taking up the residue in chloroform and chromatographing the chloroform solution of the crude product.

The Compounds I are solid at room temperature. They give positive Van Urks and Kellers color reactions in shades which differ from the corresponding reactions of the starting materials.

The Compounds I are useful as intermediates in the production of pharmaceuticals or themselves have pharmaceutical properties. The pharmaceutical compounds have a serotonin-inhibiting action so that they may be used in the treatment of psychic and rheumatic illnesses as well as of allergies, inflammations and migraine. 1- cyanoethyl-D-lysergic acid (+)-butanolamide-(2') has been found to have an especially strong serotonin-inhibiting action. An etfective amount of a Compound I is combined with an inert carrier or vehicle to provide a pharmaceutical composition in unit dosage form.

The term known as used herein designates a method described in the literature on the subject or in actual use.

In the following non-limitative examples all temperatures are stated in degrees centigrade. The melting points are corrected.

. Example I.1-cyanoethyl-6-methyl-erg0lenyl- (8) -carbamic acid diethylamid'e 0.1 g. of crystalline sodium ethylate is added to a solution of 1.6 g. of 6-methyl-ergolenyl-(8)-carbamic acid diethylamide in 50 cc. of acrylonitrile, the solution stirred for 10 minutes at 50 and then heated at reflux for 1 hour. After distilling off the major portion of acrylonitrile the mixture is shaken between chloroform and a 1% tartaric acid solution and the basic reaction products, which have been isolated in the usual manner, are chromatographed on 100 g. of aluminum oxide; The cyanoethyl compound is washed into the filtrate with chloroform containing 0.1% of alcohol. The desired cyanoethyl compound crystallizes from ethyl acetate in the shape of prisms having a melting point of 198-200".

Bimaleate: Needles from methanol. Melting point 175-176". [a] =+48 (c.=0.5 in water). Kellers color reaction: blue. Van Urks color reaction: very weak salmon color.

Example II.1-cyan0ethyl-6methyl-isoergolenyl- (8)-carbamic acid ethylester A solution of 1.9 g. of 6-methyl-isoergolenyl-(8)-carbamic acid ethylester in 50 cc. of acrylonitrile is stirred together with 110 mg. of crystalline sodium ethylate for 15 minutes at room temperature, then for half an hour at 50, a further 50 mg. of sodium ethylate are added and the mixture heated to 50 for 45 minutes. After distilling off the major portion of acrylonitrile the mixture is shaken between chloroform and a 1% tartaric acid solution whereupon the basic reaction product, which has been isolated the usual manner, is crystallized from methanol. Prisms having a melting point of 129-141 result. [a] =+280 (c. =0.5 in pyridine). Kellers color reaction: blue. Van Urks color reaction: very weak salmon color.

What is claimed is:

1. l-cyanoethyl-6-methyl-ergolenyl (8)-carbamic acid diethylamide.

2. 1-cyanoethyl-6-methyl-ergolenyl-(8) carbamic acid diethylamide bimaleate.

3. A pharmaceutically acceptable non-toxic acid addition salt of 1-cyanoethyl-6-methyl-ergolenyl-(8)-carbamic acid diethylamide.

4. 1-cyanoethyl-6-methyl-isoergolenyl (8) carbamic acid ethylester.

5. A pharmaceutically acceptable non-toxic acid addition salt of 1-cyanoethyl-G-methyl-isoergolenyl-(8)-car bamic acid ethylester.

No references cited.

NICHOLAS S. RIZZO, Primary Examiner. 

1. 1-CYANOETHYL-6-METHYL-ERGOLENYL - (8)-CARBAMIC ACID DIETHYLAMIDE. 